Alcohol dependence and HCV: mechanisms of combined CNS injury

酒精依赖与丙型肝炎：中枢神经系统联合损伤的机制

• 批准号: 8543374
• 负责人: JENNIFER M LOFTIS
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543374
• 关键词: Abstinence; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Antigens; Antiviral Agents; Antiviral Therapy; Anxiety; Behavior; Behavioral; Biological; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; Brain Injuries; Brain region; Breathalyzer Tests; CD8 Antigens; CD8B1 gene; Cell physiology; Chronic; Chronic Hepatitis C; Cognitive; Cognitive deficits; Comorbidity; Consumption; Data; Disease remission; Enzymes; Ethanol; Exposure to; Extrahepatic; Frequencies; Funding; Future; Goals; Healthcare Systems; Heavy Drinking; Hepatitis C; Hepatitis C virus; Human; Immune; Immunoassay; Immunotherapeutic agent; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-2; Intervention; Laboratories; Lead; Liver; Lymphocytic choriomeningitis virus; Measures; Mediating; Medical center; Mental Depression; Methamphetamine dependence; Migration Inhibitory Factor; Modeling; Molecular; Mus; Nerve Degeneration; Nervous System Trauma; Neuraxis; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Play; Population; Prevalence; Relapse; Research Project Grants; Risk; Role; Sampling; Specimen; Spleen; Study models; Substance abuse problem; Sucrose; Surface; Syndrome; Systemic disease; T cell response; T-Lymphocyte; Testing; Time; Translational Research; Treatment outcome; Tumor Necrosis Factor-alpha; Variant; Veterans; Viral; Viral Load result; Virus Diseases; addiction; alcohol effect; alcohol exposure; alcohol relapse; alcohol use disorder; behavior test; central nervous system injury; chemokine; chronic alcohol ingestion; cognitive function; cytokine; depressive symptoms; disturbance in affect; drug of abuse; immune activation; immunopathology; immunoreactivity; improved; insight; intravenous injection; liver injury; mouse model; multi-site trial; neuroinflammation; neuropsychiatry; novel; object recognition; phenylpyruvate tautomerase; preference; public health relevance; research clinical testing; therapeutic development; treatment trial

DESCRIPTION (provided by applicant): PROJECT SUMMARY One of the major consequences of chronic alcohol use in brain is increased inflammation that leads to neurodegeneration with associated cognitive and psychiatric impairments. Neuropsychiatric impairments persist in patients following substance abuse and are associated with poorer treatment outcomes. HCV is also associated with a variety of extrahepatic syndromes, including central nervous system (CNS) damage and neuropsychiatric impairments. However, it is unclear whether such cognitive and mood disturbances are a function of systemic disease, damaged hepatic function, or virus infection of the CNS. Animal models are needed to provide new insights into the molecular mechanisms and pathways affected by co-morbid alcohol dependence and chronic viral infection, and also those which are responsible for the persistence of neuropsychiatric impairments following abstinence and viral clearance. Our overall hypothesis is that HCV patients with co-morbid AUDs are at increased risk of brain damage that contributes to alcohol relapse risk. In humans and across species, our goal is to identify specific mechanisms by which chronic viral infection and alcohol induce abnormalities in immune cell function and contribute to persistent neuropsychiatric impairments. The following specific aims are proposed: 1) Determine the effects of HCV and alcohol use on peripheral T cell response and psychiatric function in veterans with co-morbid HCV and AUDs. Biological specimens and psychiatric data will be derived from those currently being collected for a treatment trial in veterans with HCV and co-morbid AUDs. We will obtain peripheral blood mononuclear cells and evaluate them across time for: i) phenotypic changes in T-cell populations, ii) surface and intracellular accumulation of cytokines, and iii) immunoreactivity to neuroantigens and other antigens. Blood samples will be used to measure key cytokines and chemokines, viral load, and liver enzymes. Rating scales that measure depression, anxiety, and alcohol consumption will also be used. Results from the immunoassays will be analyzed in relation to psychiatric measures, viral load, and alcohol use, as well as in relation to the findings from Aim 2. 2) Investigate the role of chronic alcohol exposure in regulating peripheral and central T-cell responses, CNS immunopathology, and behavioral signs of anxiety, depression, and cognitive impairments in mice infected with lymphocytic choriomeningitis virus (LCMV, clone 13 variant), an established model for HCV infections in humans. Mice will be chronically exposed to and dependent on ethanol administered intragastrically followed by intravenous injection of LCMV (or vehicle) to evaluate the consequences of co-morbidity. Behavioral tests will be conducted following ethanol exposure to assess anxiety, depressive-like behavior, and cognitive function. Blood, brain, and spleen samples will be collected to: i) measure blood ethanol concentrations, liver enzymes, viral titers, and key cytokines and chemokines, ii) evaluate T cell frequencies, including LCMV-specific CD8+ T cells (utilizing tetramer analysis; H-2Ld-restricted NP118), iii) calculate the percentage of CD4+, CD8+, and antigen-specific CD8+ T cells producing key cytokines (e.g., TNF- ), iv) evaluate immunoreactivity to neuroantigens, and v) assess neuroinflammation and neuronal degeneration. Examining the role of alcohol in regulating viral persistence and CNS immunopathology in LCMV-infected mice will lead to a more comprehensive understanding of co-morbid AUDs and HCV and may identify targets for future therapeutic development. If our hypotheses are supported, future studies will test our immunotherapeutic strategy that we have found reduces neuroinflammation and improves cognitive function in mouse models of methamphetamine dependence. Interventions that successfully treat alcohol induced neuropsychiatric impairments have a high likelihood of also reducing relapse rates and improving treatment outcomes.

描述（由申请人提供）： 长期饮酒的主要后果之一是炎症增加，导致神经退行性变，并伴有认知和精神障碍。药物滥用患者的神经精神损害持续存在，并与较差的治疗结果相关。HCV还与多种肝外综合征相关，包括中枢神经系统（CNS）损伤和神经精神损害。然而，目前尚不清楚这种认知和情绪障碍是否是系统性疾病、肝功能受损或CNS病毒感染的功能。需要动物模型提供新的见解的分子机制和受共病酒精依赖和慢性病毒感染的途径，也是那些负责戒酒和病毒清除后的神经精神损害的持久性。我们的总体假设是，合并AUDs的HCV患者的脑损伤风险增加，导致酒精复发风险。在人类和跨物种中，我们的目标是确定慢性病毒感染和酒精诱导免疫细胞功能异常并导致持续性神经精神障碍的特定机制。提出了以下具体目标：1）确定HCV和酒精使用对HCV和AUD共病退伍军人外周T细胞反应和精神功能的影响。生物样本和精神病学数据将来自目前正在收集的HCV和合并AUD的退伍军人治疗试验。我们将获得外周血单核细胞，并随时间评价它们的：i）T细胞群的表型变化，ii）细胞因子的表面和细胞内蓄积，以及iii）对神经抗原和其他抗原的免疫反应性。血液样本将用于测量关键细胞因子和趋化因子、病毒载量和肝酶。还将使用测量抑郁、焦虑和饮酒的评定量表。将分析免疫测定的结果与精神病学指标、病毒载量和酒精使用的关系，以及与目标2的结果的关系。2)研究慢性酒精暴露在调节淋巴细胞性脉络丛脑膜炎病毒（LCMV，克隆13变异体）感染小鼠外周和中枢T细胞反应、CNS免疫病理学以及焦虑、抑郁和认知障碍的行为体征中的作用，LCMV是一种已建立的人类HCV感染模型。小鼠将长期暴露于并依赖于乙醇灌胃给药，然后静脉注射LCMV（或溶媒），以评价共病的后果。将在乙醇暴露后进行行为测试，以评估焦虑、抑郁样行为和认知功能。将收集血液、脑和脾样品以：i）测量血液乙醇浓度、肝酶、病毒滴度和关键细胞因子和趋化因子，ii）评估T细胞频率，包括LCMV特异性CD 8 + T细胞（利用四聚体分析; H-2LD限制性NP 118），iii）计算产生关键细胞因子（例如，TNF-α），iv）评估对神经抗原的免疫反应性，和v）评估神经炎症和神经元变性。研究酒精在LCMV感染小鼠中调节病毒持久性和CNS免疫病理学的作用将导致对共病AUDs和HCV的更全面的了解，并可能确定未来治疗开发的靶点。如果我们的假设得到支持，未来的研究将测试我们的免疫策略，我们已经发现减少神经炎症和改善甲基苯丙胺依赖小鼠模型的认知功能。成功治疗酒精引起的神经精神障碍的干预措施也很有可能降低复发率并改善治疗结果。